In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.

Thirteen analogs of the psychoactive substance alpha-methyltryptamine (AMT) were tested for their ability to inhibit monoamine oxidase (MAO), an enzyme that breaks down neurotransmitters. All analogs inhibited MAO-A, with IC50 values ranging from 0.049 to 166 μM, and four also inhibited MAO-B (IC50 82–376 μM). 7-Me-AMT was the most potent MAO-A inhibitor, comparable to the known inhibitors harmine and harmaline, and acted competitively. Most analogs also inhibited MAO in human liver S9 fractions. These findings suggest that MAO inhibition by these compounds could contribute to dangerous serotonin- and adrenaline-related effects, especially when combined with other drugs that block monoamine reuptake.

Study at a glance

Abstract

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC50 values between 0.049 and 166μM, whereas four analogs inhibited also MAO-B with IC50 values between 82 and 376μM. 7-Me-AMT provided the lowest IC50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed.